Angiotensin II is formed from Angiotensin I by angiotensin converting enzyme (ACE). Angiotensin II is a component of the renin-angiotensin system. Angiotensin II receptor antagonists block the action of Angiotensin II. The present invention is believed to be generally applicable to hydrophobic Angiotensin II receptor antagonists (sartans) but will be described with particular reference to Valsartan.
Valsartan and other Angiotensin II receptor antagonists (including Candesartan, Eprosartan, Ibresartan, Losartan, Olmesartan and Telmesartan) are primarily used for the treatment of hypertension, and are effective where the patient is intolerant of ACE inhibitor therapy. They do not inhibit the breakdown of kinins and therefore are less frequently associated with the persistent dry cough and/or other side effects that limit ACE inhibitor therapy. More recently, they have been used for the treatment of heart failure in patients intolerant of ACE inhibitor therapy, (particularly candesartan, Irbesartan and losartan). Many Sartans exhibit low water solubility and are practically insoluble in water. This hinders their effective use.
Our co-pending international patent application PCT/GB03/03226 describes the formation of solid, porous beads comprising a three dimensional open-cell lattice of a water-soluble polymeric material. These are typically ‘templated’ materials formed by the removal of both water and a non-aqueous dispersed phase from a high internal phase emulsion (HIPE) which has a polymer dissolved in the aqueous phase. The beads are formed by dropping the HIPE emulsion into a low temperature fluid such as liquid nitrogen, then freeze-drying the particles formed to remove the bulk of the aqueous phase and the dispersed phase. This leaves behind the polymer in the form of a ‘skeletal’ structure. The beads dissolve rapidly in water and have the remarkable property that a water-insoluble component dispersed in the dispersed phase of the emulsion prior to freezing and drying can also be dispersed in water on solution of the polymer skeleton of the beads.
WO 2005/011636 discloses a non-emulsion based spray drying process for forming ‘solid amorphous dispersions’ of drugs in polymers. In this method a polymer and a low-solubility drug are dissolved in a solvent and spray-dried to form dispersions in which the drug is mostly present in an amorphous form rather than in a crystalline form.
Our co-pending applications GB 0501835 and GB 0613925 (filed 13 Jul. 2006) describe how materials which will form a nano-dispersion in water can be prepared, preferably by a spray-drying process. In the first of these applications the water insoluble materials is dissolved in the solvent-phase of an emulsion. In the second, the water-insoluble materials are dissolved in a mixed solvent system and co-exist in the same phase as a water-soluble structuring agent. In both cases the liquid is dried above ambient temperature (above 20 Celsius), such as by spray drying, to produce particles of the structuring agent, as a carrier, with the water-insoluble materials dispersed therein. When these particles are placed in water they dissolve, forming a nano-dispersion of the water-insoluble material with particles typically below 300 nm. This scale is similar to that of virus particles, and the water-insoluble material behaves as though it were in solution.
WO 2006/074218 (Elan Pharma International Ltd) discloses nanoparticulate forms of candesartan (particularly candisartan cilexitil). Particle sizes are disclosed from 2000 nm down to 50 nm. Methods for the production of these nanoparticles include grinding, milling, homogenisation, precipitation and supercritical gas methods.
In the present application the term ‘ambient temperature’ means 20 degrees Celsius and all percentages are percentages by weight unless otherwise specified.